Pharmacotherapy of treatment-resistant schizophrenia: a clinical perspectiveMarkus Dold,1 Stefan Leucht1,2

1Department of Psychiatry and Psychotherapy, Technical University Munich, Klinikum rechts der Isar, Munich, Germany; 2Department ofPsychiatry, University of Oxford, Oxford, UK

ABSTRACTA significant number of patients with schizophrenia do not respond adequately to an initial antipsychotic trial. As first step within a treatmentalgorithm for therapy-refractory schizophrenia ‘pseudoresistance’ should be ruled out (eg, re-evaluation of the diagnosis, comorbidities, complianceand adherence in terms of medication intake, adequate dose and treatment duration, and achievement of sufficient plasma levels). In case oftreatment resistance, two strategies that are often used in clinical routine care contain dose increase of the current administered antipsychotic drug(dose escalation, high-dose treatment) and switch to another, new antipsychotic. Although the response rates for both options are generally ratherlow, we see from the evidence-based perspective a slight advantage of the switching strategy (preferably to an antipsychotic with a differentreceptor-binding profile) compared to a high-dose treatment. After treatment failures with at least two different antipsychotic drugs, a monotherapywith clozapine is considered to be the treatment option of first choice. At present, pharmacological combination and augmentation strategies cannotbe regarded as a generally recommendable evidence-based treatment method. Antipsychotic monotherapy should be preferably sought. In case ofcombination treatment, it appears more appropriate to combine preferentially two antipsychotics with different receptor-binding profiles.Augmentation of antipsychotics with other agents should be used primarily to treat specific target symptoms.

Treatment resistance is one of the most important clinical challenges inthe pharmacological management of schizophrenia. Although preciseestimates are missing, authors assume that approximately 20–30% ofall patients with schizophrenia do not respond adequately to an initialantipsychotic trial.1 Therefore, the evaluation of therapeutic options incase of treatment resistance is highly clinically relevant. In this articlewe summarise the evidence for pharmacological treatment options intherapy-refractory schizophrenia derived from clinical trials, systematicreviews, meta-analyses and treatment guidelines. At present, a uniformdefinition of treatment resistance in the pharmacotherapy of schizophre-nia is not available.2 Most treatment guidelines require the failure of atleast two antipsychotic trials with different compounds, including atleast one second-generation antipsychotic, in adequate dose over aperiod between 2 and 8 weeks before treatment resistance can beassumed.3–5 In their review article, Suzuki et al2 evaluated the criteriathat were applied in 33 psychopharmacological studies to define treat-ment resistance. The majority of clinical trials requested non-responseto at least two previous antipsychotic trials (chlorpromazine equivalentsbetween 400 and 1000 mg/day) for at least 6 weeks. A significant pro-portion of the trials applied resistance criteria based on the strictso-called ‘Kane criteria’ which were introduced in 1988 in the contextof a double-blind, randomised trial comparing clozapine with chlorpro-mazine in treatment-resistant schizophrenia.6 In this study (the first todemonstrate the superiority of clozapine in treatment-resistant schizo-phrenia) patients had to be (1.) non-responsive to at least three periodsof treatment in the preceding 5 years with antipsychotic agents (fromat least 2 different chemical classes) at dosages equivalent to orgreater than 1000 mg/day of chlorpromazine for a period of 6 weeks,each without significant symptomatic relief, and (2.) without any periodof good functioning within the preceding 5 years. Moreover, to verifytreatment resistance, all participants had to be non-responders to a pro-spective trial with haloperidol (up to 60 mg/day) that was conductedbefore randomisation to either clozapine or chlorpromazine.

When discussing the different approaches to define treatmentresistance, it should be noted that in the past a lack of improvementprimarily in the positive symptoms of schizophrenia was considered.Other schizophrenic symptom domains and functional outcomes suchas social functioning or quality of life were not incorporated suffi-ciently. At present, long-term treatment aims (‘recovery ’) receivemore attention resulting in broader definitions of treatment resistancein schizophrenia.7

It is interesting to note that a neuroimaging study using [18F]-DOPApositron emission tomography scanning examined the underlying neuro-biological pathophysiology of resistance to antipsychotic medication bycomparing non-responsive patients with those who had respondedadequately to antipsychotics and healthy volunteers.8 In this investiga-tion, the dopamine synthesis capacity was lower in participants withtreatment-resistant schizophrenia than in those with sufficient responseto antipsychotic medication. Moreover, there was no significant differ-ence between participants with treatment-resistant schizophrenia andhealthy volunteers. These findings suggest that a medication aimed toachieve a blockade of dopamine receptors may be effective especiallyin patients who have an elevated dopamine synthesis capacity but lessefficacious in patients with relatively normal levels of dopamine synthe-sis capacity and in treatment-resistant patients.

The present review is a shorter version of a report on this topic pub-lished in German9 and also updates previous articles of our group,10 11

which had, however, a broader scope and the current one has beenentirely rewritten and amended. This report is based on a MEDLINEsearch with the keyword ‘antipsychotic*’ or ‘schizophreni*’. We aimedto give clinicians an overview of the available pharmacological treatmentoptions for treatment-resistant schizophrenia.

Operationalising treatment resistanceIf a patient does not respond adequately to the first administered anti-psychotic drug, the following steps should be considered (figure 1):1. Re-evaluation of the diagnosis of a schizophrenic disorder.

Particularly severe personality disorders, mania or depressive disor-ders with psychotic features are in their acute phase sometimes dif-ficult to distinguish from schizophrenia. Similarly, brain tumours andencephalopathies can cause psychotic states. Furthermore, sub-stance abuse might need to be ruled out. Comorbidities such asaffective disorders or obsessive-compulsive disorder should be con-sidered, as these may contribute to treatment resistance.

2. Possible non-compliance of the patient regarding medication intake.Non-compliance or non-adherence can be considered as a majorreason for non-response to antipsychotic medication. It has beenassumed that more than half of the patients do not take the pre-scribed medication correctly.12 To objectify compliance and adher-ence in terms of medication intake, plasma levels should beconsidered. The use of long-acting injectable antipsychotics cansometimes be a possibility to rule out non-adherence.

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3. Was the antipsychotic dose sufficient and the treatment durationadequate? Recommended doses, based on an international consen-sus survey, for the most frequently prescribed antipsychotic drugsare displayed in table 1.13 Patients with first-episode schizophreniaas well as older patients often require lower doses. The onset ofsymptom improvement may vary considerably between individualpatients. International pharmacological guidelines recommend aminimum medication period between 2 and 8 weeks until in case ofinsufficient response a change of the treatment strategy should beconsidered.1 3 4 The well-established theory of the delayed onset ofantipsychotic action followed by most of the guidelines has beenincreasingly discussed and critically questioned over the past years.Agid et al14 showed that the highest symptom reduction can beobserved already within the first week of medication and thendecreases consistently. All in all, the study results suggest that incase of no symptom improvement within the first 2 weeks of treat-ment in adequate dose, no long-term response to therapy can beexpected.15 Some studies even postulate that a statistically signifi-cant antipsychotic effect can already be observed within the first24 h after administration of the medication.16 Analyses of clinicaltrials in treatment-resistant schizophrenia could display that inpatients with a history of at least one non-response to antipsychotic

treatment a significant symptom reduction occurs within the first4 weeks.17

4. Side effects of antipsychotics can mask treatment response. Forexample, akathisia can be misinterpreted as mental agitation or par-kinsonism may mimic schizophrenic negative symptoms.

5. Were sufficient plasma levels achieved? Currently, there is no convin-cing evidence for a clear relationship between drug concentrationsin the blood and antipsychotic response, and an exact dose titrationguided by therapeutic drug monitoring (TDM) may be justified forclozapine, at best.13 However, plasma level measurements may beuseful in clinical practice in case of inefficacy of the medication oroccurrence of severe adverse effects even at low doses. Drug con-centration in the blood should be determined in the steady-statewhich is attained for most of the psychopharmacological drugs afterapproximately five elimination half-lives after the first medicationintake. This corresponds for most antipsychotics to 1 week afterachievement of the maintenance dose.18 Blood for drug concentra-tion measurement should be withdrawn ideally before ingestion ofthe morning dose which is usually 12–16 h (or 24 h if the drug isgiven once daily in the morning) after the last medication intake.18

Applying TDM, metabolisation abnormalities as well as insufficientcompliance of the patient can be identified or excluded as reason

Figure 1 Algorithm for thepharmacological treatment of patientswith treatment-resistant schizophrenia(modified from refs 3 and 4).

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for treatment failure. Polymorphisms in the cytochrome P450enzyme system, which is responsible for the metabolisation of mostpsychotropic drugs, can be also detected. On the one hand,increased enzyme activity can cause an accelerated metabolisationof the drugs (‘ultrarapid metaboliser’, about 1% of the population),on the other hand, reduced enzyme activity can cause a slowermetabolisation (‘poor metaboliser’, about 5% of the population). Thecompounds can therefore accumulate in the body even at very lowdoses and in some cases toxic drug-concentration levels can beachieved. The occurrence of severe adverse effects even at lowdoses can be interpreted as a sign for possible pharmacokinetic pro-blems. Moreover, potential drug interactions should be considered incase of pharmacological combination therapies. Clinically relevant inthis context is the interaction between smoking and a medicationwith drugs that are metabolised mainly by the cytochrome P450 iso-enzyme 1A2 such as the antipsychotics clozapine and olanzapine.As smoking induces this isoenzyme, the clearance of these com-pounds can be increased significantly. Therefore, a dose escalationmay be necessary to achieve the therapeutic window (the bloodconcentration in which a drug is most effective and the occurrenceof adverse effects is low).

Dose increase or switching of the antipsychotic drugIn case of non-response to an initial antipsychotic drug treatment, twostrategies that are often used in clinical routine care are a dose increaseof the current administered antipsychotic agent (dose escalation, high-dose treatment) and a switch to another, new antipsychotic drug.

Dose increaseA high-dose treatment with an increase of the antipsychotic doseabove the officially approved dose range (off-label dose, dose escal-ation) cannot be recommended as general treatment option for themanagement of treatment-resistant schizophrenia. This opinion is stated

consistently in all treatment guidelines of the international psychiatricsocieties.1 3 4 With regard to first-generation antipsychotics many clin-ical studies and systematic reviews concluded that a daily dose morethan 800–1000 mg chlorpromazine equivalents (or even lower) doesnot improve antipsychotic efficacy but is associated with an increasedincidence of especially extrapyramidal adverse effects.19 Although doseescalation cannot be advised generally, individual patients may respondto a high-dose or even off-label treatment. Applying blood monitoring ofdrugs raises the possibility of identifying patients that could probablybenefit from high-dose medication.18 Thus, for example, patients withpolymorphisms in the cytochrome P450 enzyme system which causean accelerated elimination of drugs (‘rapid metaboliser’) can probablybenefit from a dose increase when their drug concentration in theblood is below the effective therapeutic range in a standard dose.When a high-dose therapy is initiated in a patient, it should be closelyevaluated and in case of inefficacy, again a standard dose of the anti-psychotic should be sought.

Switching the antipsychotic drugAlthough a switch of the currently administered antipsychotic drug is anoften employed step in case of non-response, the question of theeffectiveness of switching from one antipsychotic drug to a second(each as monotherapy) is still open. Even though the efficacy of all offi-cially approved antipsychotic drugs is verified in positive clinical trials itmust be considered that these findings are derived from data with non-resistant patients and these results cannot be automatically extrapo-lated to participants who have no or inadequate response to previousantipsychotic medication. Ideally, to evaluate a switching strategy trialsare needed in which non-responders to antipsychotic pharmacotherapyare randomised in at least two study arms: in the intervention groupsthe participants are switched to a new antipsychotic drug (switchinggroup) and in the control group the medication is continued with theinitial antipsychotic without any dose adjustments. We found a double-blind, randomised study with such a design.20 The authors randomisednon-responders to an initial 2-week monotherapy with risperidone toeither a switch to olanzapine (10–20 mg/day, n=186) or continuing thesame dose of risperidone (2–6 mg/day, n=192) in the control group.After 10 weeks, a small but statistically significant between-group dif-ference could be identified in favour of switching to olanzapine (meandifference on the ‘Positive and Negative Syndrome Scale’: 3.5 points).In an earlier randomised study by Kinon et al,21 non-responders to a4-week monotherapy with fluphenazine 20 mg/day (n=115) were ran-domly assigned to the following study groups: continuation of the medi-cation with fluphenazine in a constant dose, dose-escalation offluphenazine to 80 mg/day or a switch to haloperidol 20 mg/day. Therewas no significant superiority for one of the three study groups.

Additionally, randomised trials without an adequate control group withcontinuation of the initial antipsychotic monotherapy have been carriedout.22–26 However, due to this methodological limitation, their findingsmust be interpreted with caution. In conclusion, there is insufficient evi-dence for clear therapeutic recommendations with regard to a switchingstrategy. Even if only moderate-to-low response rates can be expected,some patients appear to benefit from a switch of medication. From anevidence-based perspective, we see slight advantages of this strategycompared to a high-dose treatment with antipsychotics. However, itmust be considered that there are individual patients who may alsobenefit from a high-dose medication. In this regard, the medical historyof the patient must be assessed and taken into account.

For switching the antipsychotic drug, it is recommended to taper offthe dose of the first antipsychotic gradually while simultaneously thedose of the second one is titrated up gradually to its target dose(‘crossover titration’). Alternatively, the dose of the first antipsychoticcan be maintained at the same dose while the dose of the second

Table 1 Recommended doses of selected first-generation andsecond-generation antipsychotic drugs for the pharmacologicaltreatment of schizophrenia and related disorders based on aninternational consensus survey13

Drug

Recommendedstarting dose(in mg/day)

Recommendedtarget dose(in mg/day)

Recommendedmaximum dose(in mg/day)

First-generation antipsychotic drugs

Chlorpromazine100 300–600 800

Flupentixol 3 5–12 18Fluphenazine 3 5–15 20Haloperidol 3 5–10 20Perphenazine 8 12–24 42

Trifluoperazine5 10–20 35

Second-generation antipsychotic drugsAmisulpride 100 400–800 1000Aripiprazole 10 15–30 30Clozapine 25 200–500 800Olanzapine 5 10–20 30Paliperidone 3 6–9 12Quetiapine 100 400–800 1000Risperidone 2 4–6 8,5Ziprasidone 40 120–160 200Zotepine 50 100–300 400

Some groups of patients require normally lower doses for achieving response, forexample patients with first-episode schizophrenia as well as older patients.

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compound is increased gradually to a therapeutic level and only thenthe dose of the first agent will be decreased (‘overlap and taper’).1 10

Following pharmacodynamic considerations in case of switching, itseems preferable to choose a new compound with a different receptor-binding profile compared to the first administered agent (eg, a drugwith high serotonergic properties such as quetiapine, if the first com-pound was characterised by high affinities to dopamine receptors suchas amisulpride, risperidone or a first generation antipsychotic agent).Similarly, the results of the phase 1b study of the ‘Clinical AntipsychoticTrials of Intervention Effectiveness (CATIE)’27 can be interpreted in thissense.28 In this trial, non-responders to perphenazine benefited signifi-cantly more from a switch to olanzapine or quetiapine compared to ris-peridone; probably because both perphenazine and risperidone arecharacterised by high antidopaminergic properties and therefore, aswitch to a compound with a different mechanism of action seems tobe a more promising approach for perphenazine non-responders.

Pharmacotherapy with clozapineA large number of clinical trials were conducted to elucidate which anti-psychotic is characterised by the highest antipsychotic efficacy. Thesecond-generation antipsychotics clozapine, amisulpride, olanzapine andrisperidone appear to be slightly more effective in terms of anti-psychotic efficacy than the other antipsychotic drugs.29 30 However,with the exception of clozapine the differences in effect sizes are small.In a network meta-analysis comprising 212 randomised trials and atotal of 43 049 patients with schizophrenia, clozapine achieved thehighest effect size in terms of antipsychotic efficacy followed by amisul-pride, olanzapine and risperidone.30 Interestingly, studies withtherapy-resistant patients were excluded in this analysis and clozapinewas superior even in non-resistant participants. However, the authorsdiscussed that the superiority of clozapine stems mainly from compari-sons with first-generation rather than second-generation antipsychotics.Particularly, when considering the evidence for treatment-resistant

patients, clozapine is characterised by high efficacy verified in a largenumber of randomised trials. Therefore, clozapine is currently classifiedas first-line treatment in treatment-resistant schizophrenia.1 3–5 Thisadvice is corroborated by an early meta-analysis that investigated exclu-sively treatment-resistant participants and determined that only clozapinewas significantly more efficacious than first-generation antipsychotics.31

Similarly, clozapine resulted superior to other second-generation antipsy-chotics in a phase II study of the CATIE trial32 and in the ‘Cost Utility ofthe Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 2)’when analysing schizophrenic symptom improvement.33

In conclusion, based on the current evidence clozapine remains thegold standard and mainstay in the pharmacological treatment of refrac-tory schizophrenia. However, due to its risk profile (especially in terms ofagranulocytosis, which is about 1%), clozapine may be used only after atleast two failed previous treatment attempts with two other differentantipsychotics in adequate dosage and duration.1 3 4 Further importantlimitations of clozapine in comparison to other antipsychotics arise fromthe necessity of slow dose titration and weekly blood counts within thefirst 18 weeks of treatment (and subsequently every month). Especiallywhen high clozapine doses are administered, the reduced threshold forseizures must be considered. In clinical practice, mainly sedation, weightgain and hypersalivation may hamper the compliance of patients.

The role of other second-generation antipsychotics intreatment-resistant schizophreniaAlthough the efficacy of clozapine in the pharmacological managementof treatment-resistant schizophrenia is undisputed and sufficientlyproved, an ambiguity remains regarding the status of other antipsycho-tics in treatment-resistant conditions. Significant effect sizes were alsofound for the second-generation antipsychotics risperidone, olanzapine

and amisulpride.29 30 However, these data were mainly derived fromnon-resistant participants. Uncertainty still exists which antipsychoticshould be given when clozapine treatment is not tolerated or is notfeasible because of the occurrence of adverse effects. In this case,some treatment guidelines recommend explicitly a treatment preferablywith olanzapine or risperidone.1 In clinical trials with treatment-resistantpatients, both compounds were not significantly inferior in direct com-parison to clozapine and were able to achieve higher effect sizes com-pared to first-generation antipsychotics.10

Combination strategiesPharmacological combination treatment is defined as the simultaneousadministration of two drugs of the same group such as two antipsycho-tics. Although this strategy is widely used in daily clinical practice,34

the results of meta-analyses and systematic reviews are rather sober-ing. In their meta-analysis comprising 14 double-blind, randomised,placebo-controlled clozapine combination studies with second-generation antipsychotics, Taylor et al35 found a small but statisticallysignificant superiority of the combination treatment compared toplacebo. In another meta-analysis by Sommer et al,36 stratified accord-ing to the various compounds combined with clozapine, a significantpositive effect was determined only for sulpiride (based on a singletrial) but not for amisulpride, aripiprazole, risperidone and haloperidol.Barbui et al37 found a significant superiority of clozapine combinationwith second-generation drugs only for randomised open studies but notfor double-blind trials. Correll et al38 compared in their meta-analysis anantipsychotic combination with monotherapy whereas the previouslydescribed meta-analyses exclusively examined clozapine cotreatment.The combination therapy was superior to monotherapy in terms of all-cause discontinuation and dropouts due to inefficacy. However, it mustbe noted that many Chinese studies were included that did not com-prise only treatment-resistant participants. Furthermore, in thismeta-analysis a publication bias cannot be ruled out.38

Currently, clozapine is the most evaluated antipsychotic drug regardingcombination treatments. The most frequently investigated single combin-ation is that of clozapine with risperidone. From a pharmacological pointof view, it seems auspicious to combine antipsychotic agents with lowantidopaminergic properties such as clozapine with antipsychotics thatare characterised by a particularly strong affinity to dopamine receptors,such as amisulpride, sulpiride, haloperidol or risperidone. Concerning thepartial dopamine agonist aripiprazole, there is no convincing evidencethat a combination treatment with this compound causes any improve-ment in schizophrenic symptoms36 39 but it seems that cotreatmentwith aripiprazole can reduce antipsychotic-induced metabolic adverseeffects as well as elevated serum prolactin levels.39 Antipsychotic mono-therapy should be generally preferred and sought, although individualpatients can certainly benefit from a combination treatment. In this case,efficacy, drug interactions and the occurrence of adverse effects shouldbe closely monitored and, in case of inefficacy of the combination strat-egy, monotherapy should be considered again. In particular, the risk ofmetabolic side effects and all-cause discontinuation may increase signifi-cantly by administering antipsychotic combinations.40 In a retrospectiveHungarian cohort study, a switch of an antipsychotic drug (n=5480) wascompared to combination treatment with two antipsychotics (n=7901)in patients with at least one previous drug treatment failure. Prematurediscontinuation occurred significantly earlier in the combination treatmentgroup than in the switching group. Otherwise, in terms of mortality andhospitalisation rates, the pharmacological combination therapy wassuperior to monotherapy.41

Augmentation strategiesAugmentation treatment means the concomitant use of two drugs ofdifferent classes, for example the coadministration of an antipsychotic

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drug with an antidepressant, mood stabiliser or benzodiazepine. Manycompounds have been investigated as augmentor of antipsychoticswithout demonstrating convincing efficacy in treating schizophrenicsymptoms. Evaluated agents are, for example, acetylcholinesterase inhi-bitors, β-blockers, carbamazepine, lithium, valproate and memantine.10

Although benzodiazepines may be indicated in short-term treatment ofacutely agitated patients, there is no evidence for the use of benzodia-zepines as long-term adjunctive treatment to improve psychotic symp-toms.42 Sommer et al36 found in their meta-analysis a significantpositive effect of lamotrigine augmentation in clozapine-resistant schizo-phrenia but this effect disappeared in a sensitivity analysis after exclu-sion of an outlier study with high effect size and small sample size.Similarly, a significant positive effect of topiramate on schizophrenicpositive symptoms diminished after removal of an outlier study.36 Veryrecent meta-analyses support augmentation with aspirin or other drugswith effects on the immune system, but these findings are in ouropinion not yet ready for transfer into practice.43 44

As with the combination treatments, there is no sufficient evidence toadvise the general use of pharmacological augmentation strategies intreatment-resistant schizophrenia. A possible increase of adverseeffects and drug interactions must be considered. Augmentation strat-egies should be regarded preferable for the treatment of specific targetsymptoms such as benzodiazepines in highly agitated psychoticpatients45 or antidepressants for the treatment of comorbid depressivesymptoms or marked negative symptoms.46 Augmentation and com-bination treatments should be discontinued in case of inefficacy andantipsychotic monotherapy should be sought again.

Competing interests None.

doi:10.1136/eb-2014-101813

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Clinical review

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 Markus Dold and Stefan Leucht schizophrenia: a clinical perspectivePharmacotherapy of treatment-resistant

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